Abrogation of graft-vs.-leukemia activity after depletion of CD3+ T cells in a murine model of MHC-matched peripheral blood progenitor cell transplantation (PBPCT).
Using a murine transplantation model, we simulated a clinical situation in which major histocompatibility complex (MHC)-identical allogeneic peripheral blood progenitor cells (PBPCs) are transplanted for the treatment of a malignant disease that is resistant to resting natural killer (NK) cells but sensitive to cytokine-activated NK cells and T cell-mediated antitumor activity. We determined the influence of selective T cell depletion of allogeneic PBPC grafts on graft-vs.-leukemia (GVL) activity and investigated the effectiveness of ex vivo treatment with NK cell-activating cytokines to compensate for the putative loss of T cell-derived factors stimulating natural cytotoxicity. After pretreatment of Balb/c (H-2d) recipients with 7.5 Gy of total body irradiation, 2x10(7) rhG-CSF-mobilized PBPCs of splenectomized syngeneic or MHC-identical DBA (H-2d) mice were transferred. Selective T cell depletion (TCD) was performed by immunomagnetic purging with a mononoclonal antibody directed against CD3. In some experimental groups, T cell-depleted PBPCs were incubated with 200 U/mL interleukin (IL)-2 and 100 U/mL IL-12 for 24 hours. To investigate antileukemic activity in vivo, recipient mice were inoculated with 1x10(5) A20 cells (a B-lymphoblastic leukemia of Balb/c origin) 2 days before PBPC transplantation (PBPCT). After transplantation of unmanipulated allogeneic cells, 25% of the animals died with signs of graft-vs.-host disease (GVHD) but 71% were free from relapse 100 days after PBPCT. After TCD of allogeneic grafts with anti-CD3, the incidence of GVH-related mortality was below 5% but the leukemia-free survival rate was significantly (p < 0.05) decreased to 25% and thus was similar to that observed after syngeneic PBPCT (17%). When CD3-depleted grafts were incubated with IL-2 and IL-12, 45% of the animals remained free from leukemia; however, the difference was not statistically significant. Our results suggest that ex vivo activation of residual NK cells with IL-2 and IL-12 does not fully compensate for the abrogation of GVL activity after depletion of CD3+ T cells from MHC-matched PBPCT.
Uharek
L
L
Department of Internal Medicine II and Institute of Immunology, University of Kiel, Germany.
Glass
B
B
Zeis
M
M
Dreger
P
P
Steinmann
J
J
Löffler
H
H
Schmitz
N
N
D000818:Animals; D002051:Burkitt Lymphoma / Q000276:immunology* / Q000628:therapy*; D017252:CD3 Complex; D003602:Cytotoxicity, Immunologic; D000069585:Filgrastim; D006087:Graft vs Host Reaction / Q000276:immunology*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D018189:Immunomagnetic Separation; D007375:Interleukin-1 / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D007942:Leukemia, Experimental / Q000276:immunology* / Q000628:therapy; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011994:Recombinant Proteins; D013156:Splenectomy; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018183:Transplantation Chimera; D014916:Whole-Body Irradiation
D017252:CD3 Complex; D007375:Interleukin-1; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D018664:Interleukin-12; D000069585:Filgrastim